PROJECT SUMMARY Lymphatic circulation insufficiency, clinically manifested as lymphedema, is the most common post- operative complication among breast cancer patients and significantly compromises their quality of life. Breast cancer-associated lymphedema is caused by lymphatic obstruction due to lymph node dissection performed for tumor staging and prognosis, and post-operative irradiation therapy for cancer treatment. Damaged lymphatics fail to properly transport interstitial fluids, immune cells and tissue turnover molecules, all of which accumulate in the affected area, eventually causing a disfiguring and painful tissue swelling. Reported incidence of breast cancer-associated lymphedema ranges from 6% to 50%, depending on surgery types, follow-up treatments, obesity and number of resected lymph nodes. Importantly, as the breast cancer survival rate increases each year, more patients are expected to develop and suffer from lymphedema. Current challenges in managing breast cancer-related lymphedema include the lack of standardized diagnostic criteria, unpredictable onset of clinical symptoms, and the lack of effective treatments addressing the underlying molecular etiology other than physical compression. The goal of this study is to identify a molecular sign of developing lymphedema that can precisely predict and diagnose lymphatic insufficiency before the clinical symptoms appear. We propose to characterize the local free hyaluronan content in the affected tissues as a bio-signature that will not only help to set up standardized diagnostic criteria, but also to predict whether and when the disease occurs. In addition, to further extend our recent study demonstrating the therapeutic efficacy of retinoic acids (RAs) in lymphatic regeneration and lymphedema, we aim to optimize and improve the therapeutic protocol of RA to help treat lymphedema. By innovatively combining the hyaluronan-assisted early detection and RA-based molecular therapies, we aim to develop a prototype early intervention system against breast cancer-related lymphedema, and to establish an experimental foundation for potential future clinical use of free hyaluronan as a biomarker and RAs as therapeutic agents to treat human lymphedema patients.